It is now accepted that invasive cervical cancer is caused by infection with human papillomaviruses (HPVs), and that the development of an effective vaccine would reduce the incidence of this disease. HPV virus- like particles (VLPs) and vasomeres are promising vaccine candidates, A major advantage of these immunogens is the ability to induce serum neutralizing antibodies. Results from studies performed in animals have shown that parenterally administered VLPs induce serum antibodies that provide protection against disease. We have found recently that comparable responses are induced in mice after VLP oral immunization which suggests that oral vaccination against anogenital HPV disease may be feasible. The long-term goal of this proposal is to reduce the incidence of anogenital HPV disease through the development of cost-effective and easily administered oral vaccines. Specific aims include: 1) Characterization of systemic/mucosal responses in animals following VLP/capsomere mucosal immunization. Relative immunogenicities of VLPs/capsomere of multiple HPV types will be evaluated in mice, with and without adjuvant, and using alternative mucosal routes for immunization Oral immunogenicity will also be tested in non-human primates (i.e., baboon), and efficacy will be tested in a mucosal papillomavirus challenge model (i.e., COPV). 2) Elucidation of mechanisms of VLP enteral uptake and presentation to the immune system. We will determine anatomic localization and patho of uptake of VLPs introduced into the gastrointestinal tract. 3) Development of recombinant plants for HPV vaccine delivery. HPV-11 and -16 L1 and L2 sequences will be expressed in potato; oral immunogenicity of these materials will be tested in mice. 4) Development of novel vaccine formulations. HPV VLPs containing factors that may elicit and/or enhance cellular immune responses (i.e., HPV early region gene products or genetic sequences encoding immunomodulatory factors), will be developed and tested in vitro and in vivo. Results will yield information germane to the development of cost-effective easily administered oral vaccines against invasive cervical cancer and other HPV associated diseases.